We are investigating how heparan sulfate influences FGFR2b signaling in specific progenitor cell types in the epithelium. The exquisite control of growth factor function by HS is dictated by the tremendous structural heterogeneity of its sulfated modifications. It is not known how specific HS structures control growth factor-dependent progenitor expansion during organogenesis. We used bioengineered 3-O-sulfated-HS to investigate HS function. Defining the minimum saccharide sequences of HS that determine the selectivity and specificity of their function will facilitate the synthesis of small HS mimetics to specifically increase progenitor expansion in vitro. The aim of expanding salivary progenitors in vivo will be useful for tissue engineering. Using autologous adult biopsy cells, which can be expanded and/or directed in vitro, is a proposed treatment to repair damaged organs. One such strategy includes in vivo transplantation of organoids or stem cells grown in spheroid culture. While organoid and sphere formation mimics some aspects of development, they do not fully recapitulate organogenesis as the complex information provided by the surrounding niche, such as mesenchyme, blood vessels and nerves are not present. This is a major problem for the generation of complex branched organs in which coordinated branching morphogenesis of multiple cell types in the fetal microenvironment drive organ development. We are using multiple factors identified from the organ-specific fetal microenvironment, to maintain and expand multiple adult epithelial salivary progenitors. Stimulation of both mouse and human adult epithelial progenitors with ligands produced by the fetal salivary mesenchyme increases the number of cells expressing the progenitor markers in sphere cultures. Thus, the fetal microenvironment can instruct expanded adult epithelial progenitors to resume a developmental program of branching morphogenesis, recapitulating organogenesis. Thus development provides a template for regeneration, and delineation of additional secreted and physical cues from the niche will be required for tissue engineering and regenerative strategies to repair branching organs.